Improving the efficiency of the gene transfer process requires identification of the rate-limiting steps in: virus binding, fusion, stable integration and expression. Applying the principals of retroviruses as gene delivery vehicles to the transfer of therapeutic genes is key to correcting genetically based diseases of the nervous system. The vectors we employ are Gibbon ape leukemia virus (GALV)-based retroviral vectors as well as other gammaretroviral vectors. Our interest in host factors required for viral entry led to the identification of the gibbon ape leukemia virus receptor as PiT1, a ubiquitous plasma membrane phosphate transporter and more recently to the determination of this receptor's structure. PiT1 is the receptor not only for the exogenous retrovirus GALV, but also for the recently discovered endogenizing leukemogenic koala retrovirus KoRV. An endogenous virus differs from an exogenous infectious retrovirus in that it has integrated into the host germline and is inherited from host to offspring. As endogenous viruses undergoes a process of becoming a "domesticated" genetic element in the host genome thereby losing many of their pathogenic properties, properties present in GALV but not KoRV. Comparing the evolutionary relatedness of GALV and KoRV has led to the development of high titer GALV gene delivery vectors that have lost many of the deleterious properties of wild type GALV. This comparision has led to the production of high titer GALV vectors that lack the cytopathic cell fusion properties of wild type GALV and Vesicular Stomatitis Virus enveloped vectors. [unreadable] It has been previously proposed that gene delivery by retroviral vectors such as GALV actively dividing the transfer of genetic material into the target cell genome. As a result it was previously thought that cells such as neurons are resistant to infection by these vectors. We have combined our interests in retroviral entry and vector development for gene therapy to design retroviral vectors that can be used to efficiently introduce genes into neurons types likely to be useful for subsequent translational studies leading to introduction of foreign genes into the human central nervous system.